Cortical Overgrowth in a Preclinical Forebrain Organoid Model of CNTNAP2-Associated Autism Spectrum Disorder
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA730556 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14570244.fastq.gz | Fastqsanger.gz | |||
| SRR14570245.fastq.gz | Fastqsanger.gz | |||
| SRR14570246.fastq.gz | Fastqsanger.gz | |||
| SRR14570247.fastq.gz | Fastqsanger.gz | |||
| SRR14570248.fastq.gz | Fastqsanger.gz |
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Project description:We performed bulk-RNAseq on 8-week-old forebrain organoids grown from 3 patient derived cell lines and 3 control derived cell lines and subsequently of 3 technical replicates of one patient derived line and 3 technical replicates of the CRISPR rescue of this patient derived line
2021-05-18 | GSE174569 | GEO
Project description:We utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.
| S-EPMC8410758 | biostudies-literature
Project description:Interneurons are fundamental cells for maintaining the excitation-inhibition balance in the brain in health and disease. While interneurons have been shown to play a key role in the pathophysiology of autism spectrum disorder (ASD) in adult mice, little is known about how their maturation is altered in the developing striatum in ASD. Here, we aimed to track striatal developing interneurons and elucidate the molecular and physiological alterations in the Cntnap2 knockout mouse model. Using Stereo-seq and single-cell RNA sequencing data, we first characterized the pattern of expression of Cntnap2 in the adult brain and at embryonic stages in the medial ganglionic eminence (MGE), a transitory structure producing most cortical and striatal interneurons. We found that Cntnap2 is enriched in the striatum, compared to the cortex, particularly in the developing striatal cholinergic interneurons. We then revealed enhanced MGE-derived cell proliferation, followed by increased cell loss during the canonical window of developmental cell death in the Cntnap2 knockout mice. We uncovered specific cellular and molecular alterations in the developing Lhx6-expressing cholinergic interneurons of the striatum, which impacts interneuron firing properties during the first postnatal week. Overall, our work unveils some of the mechanisms underlying the shift in the developmental trajectory of striatal interneurons which greatly contribute to the ASD pathogenesis.
2023-01-12 | GSE222383 | GEO
Project description:Although early head and body overgrowth have been well documented in autism spectrum disorder (ASD), their prevalence and significance remain unclear. It is also unclear whether overgrowth affects males and females differentially, and whether it is associated with clinical outcomes later in life.To evaluate prevalence of somatic overgrowth, gender effects, and associations with clinical outcomes, head circumference, height, and weight measurements were collected retrospectively between birth and 2 years of age in toddlers with ASD (n = 200) and typically developing (TD; n = 147) community controls. Symptom severity, verbal, and nonverbal functioning were assessed at 4 years.Abnormalities in somatic growth in infants with ASD were consistent with early generalized overgrowth (EGO). Boys but not girls with ASD were larger and exhibited an increased rate of extreme EGO compared to community controls (18.0% versus 3.4%). Presence of a larger body at birth and postnatal overgrowth were associated independently with poorer social, verbal, and nonverbal skills at 4 years.Although early growth abnormalities in ASD are less common than previously thought, their presence is predictive of lower social, verbal, and nonverbal skills at 4 years, suggesting that they may constitute a biomarker for identifying toddlers with ASD at risk for less-optimal outcomes. The results highlight that the search for mechanisms underlying atypical brain development in ASD should consider factors responsible for both neural and nonneural tissue development during prenatal and early postnatal periods, and can be informed by the finding that early overgrowth may be more readily observed in males than in females with ASD.
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Project description:Autism Spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder where patients have impaired social behavior and communication, and restricted interests. Although various studies have been carried out to unveil the mechanisms associated with ASD, its pathophysiology is still poorly understood. Genetic variants on CNTNAP2 have been found and considered representative ASD genetic risk factors, and disruption of Cntnap2 causes ASD phenotypes in mice. Here, we performed an integrative multi-omics analysis by combining quantitative proteometabolomics data of Cntnap2 knockout (KO) mice with multi-omics data from ASD patients and forebrain organoids to elucidate Cntnap2-dependent molecular networks of ASD. First, we found Cntnap2-associated molecular signatures and cellular processes by conducting mass spectrometry-based proteometabolomic analysis of the medial prefrontal cortex of the Cntnap2 KO mouse model. Then, we narrowed these identified processes into bona fide ASD molecular processes by incorporating multi-omics data of ASD patients' prefrontal cortex. Further, we mapped cell-type-specific ASD networks by reanalyzing single-cell RNA-seq data of forebrain organoids derived from patients with CNTNAP2 mutation. Finally, we constructed a Cntnap2-associated ASD network model consisting of mitochondrial dysfunction, axonal impairment, and synaptic activity. Our results may shed light on understanding of the Cntnap2-dependent molecular networks of ASD.
2023-03-11 | PXD031656 | Pride
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-02-27 | GSE111176 | GEO
Project description:BackgroundComorbidity of Autism Spectrum Disorders with seizures or abnormal EEG (Autism-Epilepsy Phenotype) suggests shared pathomechanisms, and might be a starting point to identify distinct populations within the clinical complexity of the autistic spectrum. In this study, we tried to assess whether distinct subgroups, having distinctive clinical hallmarks, emerge from this comorbid condition.MethodsTwo-hundred and six individuals with idiopathic Autism Spectrum Disorders were subgrouped into three experimental classes depending on the presence of seizures and EEG abnormalities. Neurobehavioral, electroclinical and auxological parameters were investigated to identify differences among groups and features which increase the risk of seizures. Our statistical analyses used ANOVA, post-hoc multiple comparisons, and the Chi-squared test to analyze continuous and categorical variables. A correspondence analysis was also used to decompose significant Chi-squared and reduce variables dimensions.ResultsThe high percentage of children with seizures (28.2% of our whole cohort) and EEG abnormalities (64.1%) confirmed that the prevalence of epilepsy in Autism Spectrum Disorders exceeds that of the general population. Seizures were associated with severe intellectual disability, and not with autism severity. Interestingly, tall stature (without macrocephaly) was significantly associated with EEG abnormalities or later onset seizures. However, isolated macrocephaly was equally distributed among groups or associated with early onset seizures when accompanied by tall stature.ConclusionsTall stature seems to be a phenotypic "biomarker" of susceptibility to EEG abnormalities or late epilepsy in Autism Spectrum Disorders and, when concurring with macrocephaly, predisposes to early onset seizures. Growth pattern might act as an endophenotypic marker in Autism-Epilepsy comorbidity, delineating distinct pathophysiological subtypes and addressing personalized diagnostic work-up and therapeutic approaches.
| S-EPMC3781047 | biostudies-literature
Project description:Autism spectrum disorder is a construct used to describe individuals with a specific combination of impairments in social communication and repetitive behaviours, highly restricted interests and/or sensory behaviours beginning early in life. The worldwide prevalence of autism is just under 1%, but estimates are higher in high-income countries. Although gross brain pathology is not characteristic of autism, subtle anatomical and functional differences have been observed in post-mortem, neuroimaging and electrophysiological studies. Initially, it was hoped that accurate measurement of behavioural phenotypes would lead to specific genetic subtypes, but genetic findings have mainly applied to heterogeneous groups that are not specific to autism. Psychosocial interventions in children can improve specific behaviours, such as joint attention, language and social engagement, that may affect further development and could reduce symptom severity. However, further research is necessary to identify the long-term needs of people with autism, and treatments and the mechanisms behind them that could result in improved independence and quality of life over time. Families are often the major source of support for people with autism throughout much of life and need to be considered, along with the perspectives of autistic individuals, in both research and practice.
| S-EPMC8900942 | biostudies-literature
Project description:Autism spectrum disorder (ASD) is associated with noise hypersensitivity, the suboptimal extraction of meaningful signals in noisy environments. Because sensory filtering can involve distinct automatic and executive circuit mechanisms, however, developing circuit-specific therapeutic strategies for ASD noise hypersensitivity can be challenging. Here, we find that both of these processes are individually perturbed in one monogenic form of ASD, Ptchd1 deletion. Although Ptchd1 is preferentially expressed in the thalamic reticular nucleus during development, pharmacological rescue of thalamic perturbations in knockout (KO) mice only normalized automatic sensory filtering. By discovering a separate prefrontal perturbation in these animals and adopting a combinatorial pharmacological approach that also rescued its associated goal-directed noise filtering deficit, we achieved full normalization of noise hypersensitivity in this model. Overall, our work highlights the importance of identifying large-scale functional circuit architectures and utilizing them as access points for behavioral disease correction.
| S-EPMC7278896 | biostudies-literature
Project description:The aim of this study was to identify ASD vulnerability components, explore possible vulnerability subgroups, and evaluate environmental contribution to phenotypic variability. We performed PCA and cluster analysis using ASD risk factor data. We found that PC1 had a higher correlation with psychosocial stress (maternal stress, maternal education, and social class), and PC2 a higher correlation with biological factors (Psychiatric Family History and Gestational Complications). Clustering analysis of PCA scores using bootstrap approach showed two clusters. Comparing the methylome between clusters we found 11.879 DMPs (p<0.05), and their CpG sites were enriched in VMRs, most showing environmental and genetic influences. Hypermethylated probes presented higher rates in different regulatory regions associated with functional SNPs, indicating that the subgroups may have different affected regulatory regions and their liability to disease explained by common variations. Vulnerability score moderated by epigenetic clock was associated with Vineland Total score (p=0.0036, adjR2=0.31), suggesting risk factors with stress burden can influence phenotype.
2021-10-01 | GSE164563 | GEO